Revitalizing T Cell Response: The Potential of Bifunctional Anti-PD-1/IL-7 Fusion Protein in Overcoming Treg Suppression and PD-1 Resistance

A novel approach has been developed to address the limitations of anti-PD(L)1 therapy, which often fails to elicit a sustained response in many patients. This involves the creation of a second-generation PD-1 antibody, named BiCKI IL-7, by incorporating the IL-7 cytokine into its Fc region. The antibody's high affinity for the PD-1 target is designed to concentrate the therapeutic agent within the tumor microenvironment, facilitating a selective delivery of IL-7 to PD-1+ cells. The rationale behind this strategy is the differential expression of IL-7R and IL-7's preferential activation of effector T-cells (Teff) over regulatory T-cells (Treg), which is crucial for enhancing the immune response.

The results demonstrate that the bispecific antibody effectively neutralizes PD-1/PD-L1 and PD-L2 interactions and the PD-1 inhibitory signal, while also activating the IL-7R pSTAT5 pathway in T cells. The antibody shows a preference for binding to T cells that express both PD-1 and CD127, leading to a selective activation of primed T cells over PD-1-negative cells. The high affinity of the molecule for its targets was confirmed using a biosensor, which supports the concept of cis-targeting. In vitro assays revealed that the IL-7 component of the antibody synergizes with the anti-PD-1 to enhance TCR-mediated signaling through a non-canonical pathway, whereas the separate use of IL-7 and anti-PD-1 does not yield an additive effect.

Furthermore, despite a decrease in IL-7R expression with chronic Teff cell stimulation, the study showed that IL-7 can efficiently activate progenitor and some fully-exhausted human T-cells, maintaining their proliferation and survival. This activation was linked to a significant increase in IFNγ secretion, which was notably higher with the bispecific antibody compared to anti-PD-1 alone, even in non-responder patients. This suggests that the new antibody has the potential to reactivate T cells resistant to PD-1 therapy.

The study also explored the impact of the bispecific antibody on Treg functions, finding that it can abrogate Treg's suppressive capacity to inhibit the proliferation and IFNγ secretion of CD8+ Teff cells. Importantly, neither IL-7 nor the bispecific antibody stimulates Treg proliferation, unlike IL-2 and IL-15.

In conclusion, the research supports the therapeutic potential of combining IL-7 signaling with anti-PD-1 therapy to overcome resistance to PD-1 treatment. The bifunctional anti-PD1/IL-7 promotes a favorable immune balance by stimulating Teff cells and exhausted T-cells, while mitigating the suppressive functions of Tregs.

The study was presented by Aurore Morello and colleagues at the Annual Meeting of the American Association for Cancer Research in 2020.